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丙型肝炎病毒(hepatitis C virus,简称HCV)编码的多聚酶NS5B是丙肝病毒RNA复制的必需酶,已成为抗丙肝药物设计的有效靶标.基于HCV NS5B多聚酶的活性位点需要结合二价金属离子作为催化辅因子的机理,含有金属螯合模段的喹诺酮酸骨架被合理用来发现新结构的非核苷HCV抑制剂.根据喹诺酮酸抑制剂与NS5B多聚酶的结合模式,我们第一次设计在喹诺酮酸的2-位引入疏水基团,同时调节N-1,C-3和C-7位的取代基结构,运用我们发展的一锅煮新方法合成了结构多样的喹诺酮酸衍生物,并运用HCV体外感染实验系统进行抗病毒活性的评估,我们开展了系统的构效关系研究,发现了新结构类型的非核苷HCV抑制剂.这些2-芳基-1-环丙基/烯丙基喹诺酮酸衍生物在低浓度(μmol?L-1)下能有效抑制HCV病毒在宿主细胞Huh7.5.1的复制,并具有2~6倍的安全窗口,有进一步优化成抗HCV候选药物的潜力.
Hepatitis C virus (HCV) -encoded polymerase NS5B, an essential enzyme for hepatitis C virus RNA replication, has become a valid target for anti-hepatitis C drug design.An active site based on the HCV NS5B polymerase needs to bind to divalent metal ions as Catalytic cofactor mechanism, the quinolone acid framework containing the metal chelating moiety is reasonably used to discover novel structures of non-nucleoside HCV inhibitors.According to the binding mode of quinolone inhibitor and NS5B polymerase, we first designed a quinolone acid The introduction of a hydrophobic group at the 2-position, while adjusting the structure of the substituents N-1, C-3 and C-7 positions, the use of our development of a new one-pot method of the synthesis of a variety of quinolonic acid derivatives and the use of HCV in vitro infections An experimental system for the evaluation of antiviral activity, we conducted a systematic study of the structure-activity relationship and found novel non-nucleoside HCV inhibitors of the structure type These 2-aryl-1-cyclopropyl / allylquinolonic acid derivatives At low concentration (μmol? L-1), it can effectively inhibit the replication of HCV in Huh7.5.1 host cells and has 2 ~ 6 times of safety window, which has the potential to further optimize as an anti-HCV drug candidate.